Process for preparation of apalutamide

ABSTRACT

The present invention relates to a process for the preparation of apalutamide. In particular, the present invention relates to a process for the preparation of apalutamide and its intermediates. The present invention also relates to pharmaceutical compositions comprising apalutamide.

CROSS REFERENCE APPLICATION

This application is a continuation-in-part of U.S. Ser. No. 16/366,283filed Mar. 27, 2019, which claims the benefit of Indian ApplicationsNos.: 201821011729 filed Mar. 28, 2018 and 201921000421 filed Jan. 4,2019, the content of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a process for the preparation ofapalutamide. In particular, the present invention relates to a processfor the preparation of apalutamide and its intermediates. The presentinvention also relates to pharmaceutical composition comprisingapalutamide.

BACKGROUND OF THE INVENTION

The following discussion of the prior art is intended to present theinvention in an appropriate technical context and allow its significanceto be properly appreciated. Unless clearly indicated to the contrary,however, a reference to any prior art in this specification should beconstrued as an admission that such art is widely known or forms part ofcommon general knowledge in the field.

Apalutamide is an androgen receptor inhibitor, indicated for thetreatment of non-metastatic castration-resistant prostate cancer,represented as Formula (I).

U.S. Pat. No. 8,445,507 B2 (the U.S. '507 patent) discloses hydantoincompounds and methods for synthesizing them and using them forpreventing or treating a hyperproliferative disorder, such as hormonesensitive prostate cancer or hormone refractory prostate cancer. TheU.S. '507 B2 discloses a process for the preparation of apalutamide asdepicted in Scheme-1.

The prior art U.S. '507 B2, discloses the coupling of compound A andcompound B with the application of microwave in a polar solvent and withheating to a temperature of about 80° C.

U.S. P.G-Pub. No. 2018/0201601 A1 (the U.S. '601 A1) discloses a processfor the preparation of Apalutamide by following reaction scheme:

wherein R is C₁-C₆ alkyl.

There is still a need to provide an alternative process for thepreparation of apalutamide.

SUMMARY OF THE INVENTION

In one general aspect, there is provided a process for the preparationof apalutamide of Formula (I),

the process comprising:reacting compound of Formula (II′) or salts thereof,

wherein R is hydrogen or C₁-C₅ alkyl,with compound of Formula (III),

optionally in the presence of an alcohol or a phenol or mixture thereofto obtain apalutamide.

In another general aspect, there is provided a process for thepreparation of compound Formula (II′) or salts thereof,

the process comprising:reacting compound of Formula (IV) with compound of Formula (V); and

wherein,R₁ and R₂ are either halogen or amine and interchangeable, with theproviso that both R₁ and R₂ are not same, wherein halogen is F, Cl, Bror I;R is hydrogen or C₁-C₅ alkyl;optionally, converting the compound of Formula (II′) to salts thereof.

In another general aspect, there is provided compound of Formula (II′),or salts thereof,

wherein R is hydrogen or C₁-C₅ alkyl.

In another general aspect, there is provided salts of compound ofFormula (II′) and its use for the preparation of apalutamide.

In another general aspect, there is provided a process for thepreparation of salts of compound of Formula (II′) and its use for thepreparation of apalutamide. The process comprising reacting compound ofFormula (II′) with a base in a suitable solvent to obtain salt ofcompound Formula (II′).

In another general aspect, there is provided a process for isolation ofcompound of Formula (III) in solid form and its use for the preparationof apalutamide.

In another general aspect, there is provided a substantially pureapalutamide.

In another general aspect, there is provided an apalutamide of Formula(I) substantially free from diketo-impurity-A.

In another general aspect, there is provided an apalutamide of Formula(I) substantially free from desflouro-impurity-B.

In another general aspect, there is provided an apalutamide of Formula(I) substantially free from one or more of impurities when measured byarea percentage of HPLC.

In another general aspect, there is provided a pharmaceuticalcomposition comprising substantially pure apalutamide together with oneor more of pharmaceutically acceptable carriers, excipients, anddiluents.

In another general aspect, there is provided a pharmaceuticalcomposition comprising apalutamide substantially free from one or moreof impurities together with one or more of pharmaceutically acceptablecarriers, excipients, and diluents.

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1: XRD of triethylamine salt of compound of Formula (II)

FIG. 2: DSC thermogram of triethylamine salt compound of Formula (II)

FIG. 3: TGA of triethylamine salt compound of Formula (II)

FIG. 4: XRD of compound of Formula (III)

FIG. 5: DSC thermogram of compound of Formula (III)

DETAILED DESCRIPTION OF THE INVENTION

All ranges recited herein include the endpoints, including those thatrecite a range “between” two values. Terms such as “about”, “generally”,and “substantially,” are to be construed as modifying a term or valuesuch that it is not an absolute. This includes, at very least, thedegree of expected experimental error, technique error and instrumenterror for a given technique used to measure value.

The terms such as “treating”, “reacting”, and “condensing” have meaningsas widely used by general prior art in the field of invention and can beeasily understood by those skilled in the art.

The product(s) obtained may further be dried additionally to achieve thedesired level of moisture and/or residual solvents. The product(s)obtained may further be converted to any other physical forms thereofwhich include but not specifically limited to polymorph(s), salt(s),solvate(s), hydrate(s), co-crystal(s) or solid dispersion(s); andcrystalline or amorphous forms thereof.

In general, the term “substantially free” means apalutamide havingpurity of about 98% or more having each one or more of impurities lessthan 0.15% or less by area percentage of HPLC. In particular, theapalutamide prepared the present invention is having purity of about 98%or more, 99% or more, 99.5% or more, 99.8% or more, 99.9% or more andhaving diketo impurity-A of about 0.15% or less, 0.10% or less, 0.05% orless or not in detectable amount, when measured by area percentage ofHPLC.

The term “substantially pure” herein means apalutamide having a purityof at least about 98% by area percentage of HPLC. In particular,apalutamide having a purity of at least about 99%, more particularly, apurity of at least about 99.5%, further more particularly, a purity ofat least about 99.8%, most particularly, a purity of at least about99.9% by area percentage of HPLC.

As used herein, the term “solution” or “reaction mixture” does not limitto a clear solution only and includes any hazy or opaque mass obtained.

The term “pharmaceutical composition” is intended to encompass a drugproduct including the active ingredient(s), pharmaceutically acceptableexcipients that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients. Accordingly, thepharmaceutical compositions encompass any composition made by admixingthe active ingredient, active ingredient dispersion or composite,additional active ingredient(s), and pharmaceutically acceptableexcipients.

The terms used throughout the description is defined herein below.

“TEA” refers to triethylamine.

“TBA” refers to ten-butyl amine.

“DIPA” refers to diisopropyl amine.

“DIPEA” refers to diisopropyl ethylamine.

“DBU” refers to 1,8-diazabicyclo[5.4.0]undec-7-ene.

“DABCO” refers to 1,4-diazabicyclo[2.2.2]octane.

“DBN” refers to 1,5-Diazabicyclo[4.3.0]non-5-ene

“HPLC” refers to high performance liquid chromatography.

In one general aspect, there is provided a process for the preparationof apalutamide of Formula (I),

the process comprising:reacting compound of Formula (II′) or salts thereof,

wherein R is hydrogen or C₁-C₅ alkyl,with compound of Formula (III),

optionally in the presence of an alcohol or a phenol or mixture thereofto obtain apalutamide.

In another general aspect, there is provided a process for thepreparation of compound

Formula (II') or salts thereof,

the process comprising:reacting compound of Formula (IV) with compound of Formula (V); and

wherein,R₁ and R₂ are either halogen or amine and interchangeable, with theproviso that both R₁ and R₂ are not same, wherein halogen is F, Cl, Bror I;R is hydrogen or C₁-C₅ alkyl;optionally, converting the compound of Formula (II′) to salts thereof.

In another general aspect, there is provided a process for thepreparation of apalutamide of Formula (I),

the process comprising:reacting triethylamonium salt compound of Formula (IIs),

with compound of Formula (III),

optionally in the presence of an alcohol or a phenol or mixture thereofto obtain apalutamide.

In general, the compound of Formula (IV) is reacted with compound ofFormula (V) optionally in the presence of a base, in one or moresolvents to obtain compound of Formula (II).

The base comprises of inorganic or organic base. The inorganic basecomprises one or more of sodium hydroxide, potassium hydroxide, lithiumhydroxide; sodium carbonate, potassium carbonate, sodium bicarbonate,potassium bicarbonate; and ammonia or its aqueous solution; or theorganic base comprises one or more of TEA, TBA, DIPA, DIPEA, pyridine,piperidine, morpholine, DBU, DABCO and DBN. In particular, TEA may beused.

The solvent comprises one or more of esters selected from ethyl acetate,isopropyl acetate, t-butyl acetate, and isobutyl acetate; hydrocarbonsselected from toluene, xylene, ethyl benzene, heptane, hexane, andcyclohexane; chlorinated solvents selected from chloroform, methylenedichloride, ethylene dichloride, chlorobenzene, chloroform, and carbontetrachloride. In particular, toluene, xylene, methylene dichloride, andethyl acetate may be used.

In general, the purification of compound (II) may be performed in one ormore of solvents. The solvent comprises one or more of ketones selectedfrom acetone, methyl isobutyl ketone, and methyl ethyl ketone; estersselected from ethyl acetate, isopropyl acetate, t-butyl acetate, andisobutyl acetate; chlorinated solvents selected from methylenedichloride, ethylene dichloride, and chlorobenzene; and water. Inparticular, water, methanol, acetone, ethyl acetate, methylenedichloride may be used. More particularly, water is used.

In general, the compound of Formula (III) can be prepared by reacting5-amino-3-(trifluoromethyl)picolinonitrile with thiophosgene in thepresence of a solvent. The solvent comprises one or more of ketonesselected from acetone, methyl isobutyl ketone, and methyl ethyl ketone;esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate,and isobutyl acetate; chlorinated solvents selected from chloroform,methylene dichloride, ethylene dichloride, and chlorobenzene. hiparticular, a mixture of methylene dichloride and water may be used.

In general, the salts of compound of Formula (II′) may be prepared byreacting compound of Formula (II′) with base, optionally in the presenceof one or more solvents.

The salts of compound Formula (II′) may include salts with inorganicbases such as sodium hydroxide, potassium hydroxide, lithium hydroxide;sodium carbonate, potassium carbonate, sodium bicarbonate and potassiumbicarbonate; or the organic base comprising one or more of TEA, TBA,DIPA, DIPEA, pyridine, piperidine, morpholine, DBU, DABCO and DBN; orthe inorganic acids such as hydrochloric acid, sulfuric acid, nitricacid, perchloric acid, phosphoric acid; or the organic acids such asacetic acid, oxalic acid, citric acid, formic acid. In particular, TEAmay be used.

In general, the apalutamide of Formula (I) may be prepared by reactingthe compound of Formula (II′) or its salts with the compound of Formula(III), optionally in the presence of a base in one or more solvents.

In general, the base comprises of inorganic or organic base. Theinorganic base comprises one or more of sodium hydroxide, potassiumhydroxide, lithium hydroxide; sodium carbonate, potassium carbonate,sodium bicarbonate, and potassium bicarbonate; or the organic basecomprises one or more of TEA, TBA, DIPA, DIPEA, pyridine, piperidine,morpholine, DBU, DABCO and DBN. In particular, TEA may be used.

In general, the solvent comprises of one or more of esters selected fromethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate;hydrocarbons selected from toluene, xylene, ethyl benzene, heptane,hexane, and cyclohexane; chlorinated solvents selected from methylenedichloride, ethylene dichloride, chlorobenzene, chloroform, and carbontetrachloride. In particular, toluene, xylene, methylene dichloride, andethyl acetate may be used.

The prior art U.S. '507 B2, discloses the coupling of compound A andcompound B with application of microwave in a polar solvent and withheating to a temperature of about 80° C. The present invention hasadvantages over the prior art. The process is simple and doesn't involveuse of microwave.

In general, the reaction of compound (II) and compound (III) may beperformed at temperature ranging from 25° C. to boiling point of thesolvent(s). In particular, the reaction may be performed at 25° C. to150° C. Alternatively, the reaction may also be performed under cooledconditions having temperature from −25° C. to about 25° C. Inparticular, from −10° C. to about 10° C.

In general, the present invention provides the preparation ofapalutamide wherein the reaction of the compound (II′) and the compound(III) is done in presence of an alcohol or phenol. The alcohol or phenolarrest the formation of impurity-A during the reaction and therebyprovide apalutamide substantially free from impurity-A.

In general, the alcohol or phenol is selected from2,2,2-trifluoroethanol, methanol, ethanol, n-propyl alcohol, isopropylalcohol, cyclohexanol, isobutyl alcohol, tort-amyl alcohol, butanol,pentanol, hexadecanol, ethane-1,2-diol, propane-1,2-diol, phenol,cresol, or mixture thereof. In particular, 2,2,2-trifluoro ethanol maybe used.

The compound of Formula (D i.e. apalutamide may be isolated by usualwork-up wherein the solvent after completion of the reaction may beremoved by filtration or evaporation.

Alternatively, the solvent may be distilled to obtain residue which maybe extracted with one or more solvents selected from dimethylformamide,dimethylacetamide, dimethylsulfoxide, N-methyl pyrrolidone,tetrahydrofuran, acetonitrile, ethylacetate, toluene, and xylene. Thereaction mixture may be acidified with an acid selected fromhydrochloric acid, sulfuric acid, acetic acid, or formic acid, therebyto adjust the acidic pH.

In general, the purification of apalutamide is done in one or more ofsolvents. The organic solvents comprise one or more of alcohols selectedfrom methanol, ethanol, isopropanol, butanol, t-butanol, andisoamylalcohol; ketones selected from acetone, methyl isobutyl ketone,and methyl ethyl ketone; esters selected from ethyl acetate, isopropylacetate, t-butyl acetate, and isobutyl acetate; chlorinated solventsselected from methylene dichloride, ethylene dichloride, andchlorobenzene. In particular, methanol, acetone, ethyl acetate,methylene dichloride may be used.

In another general aspect, there is provided a compound of Formula(II′), or salts thereof,

wherein R is hydrogen or C₁-C₅ alkyl.

In another general aspect, there is provided salts of compound ofFormula (II′) and its use for the preparation of apalutamide.

In another general aspect, there is provided an isolated compound ofFormula (II′), or salts thereof.

In another general aspect, there is provided an isolated compound ofFormula (II):

In general, the compound of Formula (II) may be isolated by usualwork-up wherein the solvent after completion of the reaction may beremoved by filtration or evaporation. Alternatively, the solvent may bedistilled to obtain residue which may be extracted with one or moresolvents selected from water, dichloromethane, chloroform,dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, ethylacetate, toluene, andxylene. The reaction mixture may be acidified with an acid selected fromhydrochloric acid, sulfuric acid, acetic acid, or formic acid, therebyto adjust the acidic pH.

In another general aspect, there is provided a salt compound of Formula(IIs):

In general, the salt compound of Formula (IIs) of the present inventionis crystalline, characterized by x-ray powder diffraction pattern havingpeaks expressed in terms of 2θ at about 6.7°, 12.0° and 13.5°±0.2. Itcan be further characterized by peaks expressed in terms of 2θ at about9.3°, 17.5°, 21.1° and 21.2°±0.2. The XRD, DSC, and TGA of compound ofFormula (II) as triethylamine salt is depicted in FIGS. 1, 2 & 3.

In another general aspect, there is provided a process for thepreparation of salts of compound of Formula (II′) and its use for thepreparation of apalutamide. The process comprising reacting compound ofFormula (II′) with a base in a suitable solvent to obtain salt ofcompound Formula (II′).

The salts of compound Formula (II′) may include salts with inorganicbases such as sodium hydroxide, potassium hydroxide, lithium hydroxide;sodium carbonate, potassium carbonate, sodium bicarbonate and potassiumbicarbonate; or the organic base comprising one or more of TEA, TBA,DIPA, DIPEA, pyridine, piperidine, morpholine, DBU, DABCO and DBN; orthe inorganic acids such as hydrochloric acid, sulfuric acid, nitricacid, perchloric acid, phosphoric acid; or the organic acids such asacetic acid, oxalic acid, citric acid, formic acid. In particular, TEAmay be used.

In another general aspect, there is provided a process for isolation ofcompound of Formula (III) in solid form and its use for the preparationof apalutamide.

In another general aspect, there is provided a process for isolation ofcompound of Formula (III) in solid form through crystallization.

The solvent used for crystallization may include non-polar solvents suchhexane;

cyclohexane, heptane; toluene or polar solvents such as acetone,ethanol, diethyl ether, methyl tertiary butyl ether or butanol. The XRDand DSC of compound of Formula (III) is depicted in FIGS. 4 & 5.

In general, the compound of Formula (III) of the present invention ischaracterized by x-ray powder diffraction pattern having peaks expressedin terms of 2θ at about 15.1°, 17.7°, 19.9° and 20.9°±0.2. It can befurther characterized by peaks expressed in terms of 2θ at about 7.3°,15.1°, 16.1°, 22.8°, 26.1°, 26.7° and 27.1°±0.2.

In general, the compound of Formula (III) of the present invention ischaracterized by DSC. DSC measures the difference in heat energy uptakebetween a sample and an appropriate reference with increase intemperature. The DSC thermogram for compound of Formula (III) is shownin FIG. 5 and described in example 8, indicates an endothermic peak atabout 39.1° C.

In another general aspect, there is provided a substantially pureapalutamide.

In another general aspect, there is provided a process for thepreparation of apalutamide of Formula (I),

the process comprising:reacting a compound of Formula (IV) with a compound of Formula (V) toobtain compound of Formula (II′);

wherein, R₁ and R₂ are either a leaving group or amine andinterchangeable, with a proviso that both R₁ and R₂ are not same, andwherein the leaving group is F, Cl, Br or I, OTs, OTf, OMs,optionally, converting the compound of Formula (II′) to salts thereof;reacting 5-amino-3-(tri fluoromethyl)picolinonitrile with thiophosgeneto obtain compound of Formula (III); and

reacting the compound of Formula (III) in-situ with the compound ofFormula (II′) or salts thereof in the presence of an alcohol or phenolto obtain apalutamide of Formula (I).

In general, the compound of Formula (II′) or salts thereof is thecompound of Formula (IIs),

In general, the compound of Formula (III) is not isolated and reactedin-situ with compound of Formula (II′) or salts thereof in the presenceof alcohol or phenol selected from 2,2,2-trifluoroethanol methanol,ethanol, n-propyl alcohol, isopropyl alcohol, cyclohexanol, isobutylalcohol, tert-amyl alcohol, butanol, pentanol, hexadecanol,ethane-1,2-diol, propane-1,2-diol, phenol, cresol, or mixture thereof.

In general, the impurities of apalutamide may be one or more ofimpurity-A or impurity-B represented by structural formula as hereinbelow:

In another general aspect, there is provided an apalutamide of Formula(I) substantially free from diketo-impurity-A.

In another general aspect, there is provided an apalutamide of Formula(I) substantially free from desflouro-impurity-B.

In general, the starting compound (II), wherein R is hydrogen, is thepotential source for the formation of desflouro-impurity-B. Preparationof salt of compound of Formula (II) provides compound of Formula (II) inits salt form substantially free from impurities. The presence of higheramount of desfluoro analouge of the compound (II) results in highercontent of impurity-B, when measured by area percentage of HPLC.

The use of starting material compound (H) containing desfluoro analogueof about 0.15% or less, results in apalutamide containingdesfluoro-impurity-B of about 0.15% or less by area percentage of HPLC.

In general, the starting material compound (II) or its salt containingdesfluoro analogue of about 0.15% or less, in particular, containing0.10% or less, more particular, containing 0.05% or less, mostparticularly containing not in detectable amount may be used to obtainapalutamide substantially free from desfluoro-impurity-B.

In another general aspect, there is provided an apalutamide of Formula(I) substantially free from one or more of impurities when measured byarea percentage of HPLC.

In another general aspect, there is provided a pharmaceuticalcomposition comprising substantially pure apalutamide together with oneor more of pharmaceutically acceptable carriers, excipients, anddiluents.

In another general aspect, there is provided a pharmaceuticalcomposition comprising apalutamide substantially free from one or moreof impurities together with one or more of pharmaceutically acceptablecarriers, excipients, and diluents.

The present invention is further illustrated by the following examplewhich is provided merely to be exemplary of the invention and do notlimit the scope of the invention.

EXAMPLES Example-1: Preparation of1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-cyclobutane-1-carboxylicAcid

In a 500 mL four necked round bottomed flask equipped with nitrogenatmosphere facility, mechanical stirrer, thermometer and an additionfunnel, (20 g) 4-amino-2-fluoro-N-methylbenzamide, (25.6 g)1-bromocyclobutane-1-carboxylic acid and 200 mL chloroform were added atroom temperature. (40 mL) triethylamine was added and the reactionmixture was stirred for 15 hours at 60-65° C. After the completion ofthe reaction, the reaction mixture was cooled to 25-35° C. and 20 mLwater followed by addition of 20 mL hydrochloric acid and stirred for 2hours, filtered, washed with 25 mL water and dried to obtain 20.1 gtitled compound with 98.85% purity by HPLC.

Example-2: Preparation of1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-cyclobutane-1-carboxylicAcid

In a 500 mL four necked round bottomed flask equipped with nitrogenatmosphere facility, mechanical stirrer, thermometer and an additionfunnel, (10 g) 4-amino-2-fluoro-N-methylbenzamide, (12.8 g)-bromocyclobutane-1-carboxylic acid and 100 mL chloroform were added atroom temperature. (15 g) triethylamine was added and the reactionmixture was stirred for 15 hours at 60-65° C. After the completion ofthe reaction, the reaction mixture was cooled to 25-35° C. and 10 mLhydrochloric acid was added and stirred for 2 hours, filtered, washedwith 25 mL water and dried to obtain 10.2 g titled compound with 97.99%purity by HPLC.

Example-3: Preparation of1-((3-fluoro-4-(methylcarbamoyflphenyDamino)-cyclobutane-1-carboxylicAcid

In a 500 mL four necked round bottomed flask equipped with nitrogenatmosphere facility, mechanical stirrer, thermometer and an additionfunnel, (10 g) 4-amino-2-fluoro-N-methylbenzamide, (16 g)1-bromocyclobutane-1-carboxylic acid and 100 mL dichloromethane wereadded at room temperature. (25 mL) triethylamine was added and thereaction mixture was stirred for 15 hours at 20-30° C. After thecompletion of the reaction, the reaction mixture was concentratedcompletely U/V at 40° C. 100 mL water was added and stirred for 1 hour.7.5 mL hydrochloric acid was added and stirred for 30 min. The reactionmixture was cooled to 0-5° C. and stirred for 1 hour, filtered, washedwith 25 mL water and dried to obtain 15 g titled compound with 94.05%purity by HPLC.

Example-4: Purification of1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-cyclobutane-1-carboxylicAcid

In a 500 mL four necked round bottomed flask equipped with nitrogenatmosphere facility, mechanical stirrer, thermometer and an additionfunnel, (15 g) title compound of example-1 and 120 mL acetone wereheated to 55 to 60° C. for 1 hour. The reaction mixture was cooled to 0to 5° C. and the product thus obtained was filtered and dried undervacuum at 50° C. to obtain 12.1 g titled compound with 99.50% purity byHPLC.

Example-5: Preparation of1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-cyclobutane-1-carboxylateTriethylammonium

In a 500 mL four necked round bottomed flask equipped with nitrogenatmosphere facility, mechanical stirrer, thermometer and an additionfunnel, (18 g)1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutane-1-carboxylicacid, 270 mL ethyl acetate and 18 mL triethylamine were added at roomtemperature. The reaction mixture was stirred for 2 hours at 25 to 35°C., filtered, washed with 36 mL ethyl acetate and dried to obtain 23.93g titled compound with 99.81% purity by HPLC.

Example-6: Preparation of1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-cyclobutane-1-carboxylateTriethylammonium

In a 500 mL four necked round bottomed flask equipped with nitrogenatmosphere facility, mechanical stirrer, thermometer and an additionfunnel, (10 g)1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutane-1-carboxylicacid, 100 mL ethyl acetate and 10 mL triethylamine were added at roomtemperature. The reaction mixture was stirred for 2 hours at 25 to 35°C., filtered, washed with 25 mL ethyl acetate and dried to obtain 16 gtitled compound with 99.7% purity by HPLC.

Example-7: Preparation of1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-cyclobutane-1-carboxylatePotassium

In a 500 mL four necked round bottomed flask equipped with nitrogenatmosphere facility, mechanical stirrer, thermometer and an additionfunnel, (10 g)1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutane-1-carboxylicacid, 100 mL ethyl acetate and 5 g of potassium hydroxide dissolved in10 mL water were added at room temperature. The reaction mixture wasstirred for 2 hours at 25 to 35° C., filtered, washed with 25 mL ethylacetate and dried to obtain 16 g titled compound with 99.7% purity byHPLC.

Example-8: Preparation of5-isothiocyanato-3-(trifluoromethyl)picolinonitrile

In a 500 mL four necked round bottomed flask equipped with nitrogenatmosphere facility, mechanical stirrer, thermometer and an additionfunnel, (20 g) 5-amino-3-(trifluoromethyl)picolinonitrile, 200 mL waterand 100 mL dichloromethane were added at 20-30° C. The reaction mixturewas stirred for 15 min and 20 mL thiophosgene was added. The reactionmixture was stirred for 4 hours. After completion of the reaction, thelayers were separated. Organic layer washed with 100 mL 8% sodiumbicarbonate solution and the organic layer was concentrated completelyU/V at 40° C. 140 mL n-hexane was added to the concentrated reactionmass and cooled 0 to 5° C. The compound was filtered, washed with hexaneand dried to obtain as solid 20 g titled compound with 96.52% purity byHPLC.

Example-9: Preparation of5-isothiocyanato-3-(trifluoromethyl)picolinonitrile

In a 500 mL four necked round bottomed flask equipped with nitrogenatmosphere facility, mechanical stirrer, thermometer and an additionfunnel, (15 g) 5-amino-3-(trifluoromethyl)picolinonitrile, 150 mL waterand 75 mL dichloromethane were added at 20-30° C. The reaction mixturewas stirred for 15 min and 9 mL thiophosgene was added. The reactionmixture was stirred for 4 hours. After completion of the reaction, thelayers were separated and the organic layer was concentrated completelyU/V at 40° C. 105 mL hexane was added to the concentrated reaction massand cooled 0 to 5° C. The compound was filtered, washed with hexane anddried to obtain 19.85 g titled compound.

Example-10: Preparation of Apalutamide

In a 1000 mL four necked round bottomed flask equipped with nitrogenatmosphere facility, mechanical stirrer, thermometer, condenser and anaddition funnel (16 g)5-isothiocyanato-3-(trifluoromethyDpicolinonitrile and 200 mL chloroformwere added. (10 g) phenol was added into the reaction mixture. Thereaction mixture was stirred for 15 min. The reaction mixture was heatedto 60 to 65° C. A solution of (20 g)1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutane-1-carboxylatetriethylammonium in 200 mL chloroform was added slowly at 60 to 65° C.The reaction mixture was refluxed for 3 hours. After the completion ofthe reaction, the reaction mixture was washed by 100 mL water andconcentrated the organic layer completely at 50° C. U/V. 180 mL methanolfollowed by 60 mL water were added to the concentred reaction mass andstirred for 3 hours at 25-35° C. The compound was filtered, washed with20 mL of methanol and 20 mL water mixture and dried to obtain 17 g ofApalutamide with 98.81% purity by HPLC.

Example-11: Purification of Apalutamide

In a 500 mL four necked round bottomed flask equipped with nitrogenatmosphere facility, mechanical stirrer, thermometer and an additionfunnel (15 g) Apalutamide and (105 mL) methanol were added at 20-30° C.The reaction mixture was heated to reflux to obtain clear solution. Thereaction mixture was cooled to 0 to 5° C. and stirred for 1 hour. TheApalutamide was filtered, washed with 30 mL methanol and dried to obtain11.2 g Apalutamide with 99.82% purity having 0.01% of diketo impurityand 0.03% of single maximum unknown impurity by HPLC.

Example-12: Preparation of Apalutamide

In a 50 mL four necked round bottomed flask equipped with nitrogenatmosphere facility, mechanical stirrer, thermometer and an additionfunnel (1 g)1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutane-1-carboxylatetriethylammonium and 10 mL chloroform were added. (1 g) phenol was addedin to the reaction mixture. The reaction mixture was stirred for 15 min.The reaction mixture was heated to reflux. A solution of (1 g)5-isothiocyanato-3-(trifluoromethyl)5 picolinonitrile in 10 mLchloroform was added slowly. The reaction mixture was refluxed for 6hours. After the completion of the reaction, the reaction mixture wasconcentrated completely at 50° C. U/V. 20 mL isopropyl alcohol was addedto the concentred reaction mass and stirred for 3 hours at 20-30° C. Thecompound was filtered, washed with 2 mL of isopropyl alcohol and driedto obtain 1 g of Apalutamide with 99.18% purity by HPLC having diketoimpurity-A <0.15.

Example-13: Preparation of Apalutamide

In a 50 mL four necked round bottomed flask equipped with nitrogenatmosphere facility, mechanical stirrer, thermometer and an additionfunnel (1 g)1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutane-1-carboxylatetriethylammonium and 10 mL chloroform were added. The reaction mixturewas heated to reflux. A solution of (1 g)5-isothiocyanato-3-(trifluoromethyl)picolinonitrile in 10 mL chloroformwas added slowly. The reaction mixture was refluxed for 6 hours. Afterthe completion of the reaction, the reaction mixture was concentratedcompletely at 50° C. U/V. 20 mL isopropyl alcohol was added to theconcentred reaction mass and stirred for 3 hours at 20-30° C. Thecompound was filtered, washed with 2 mL of isopropyl alcohol and driedto obtain 0.9 g of Apalutamide with 98.5% purity and having 0.5% ofdiketo impurity-A by HPLC.

Example-14: Preparation of Apalutamide in Absence of Phenol

In a 500 mL four necked round bottomed flask equipped with nitrogenatmosphere facility, mechanical stirrer, thermometer and an additionfunnel (14 g) 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile and150 mL chloroform were added. The reaction mixture was stirred for 15min and 5 mL triethylamine was added at 20-30° C. The reaction mixturewas heated to reflux for 15 min. (10 g)1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutane-1-carboxylicacid was added. The reaction mixture was refluxed for 6 hours. After thecompletion of the reaction, the reaction mixture was concentratedcompletely at 50° C. U/V. 20 mL isopropyl alcohol was added to theconcentered reaction mass and stirred for 60 min at 20-30° C. Thecompound was filtered, washed with 2 mL of isopropyl alcohol and driedto obtain 13.7 g of apalutamide with 98.68% purity by HPLC.

Example-15: Preparation of Apalutamide in Presence of Phenol

In a 500 mL four necked round bottomed flask equipped with nitrogenatmosphere facility, mechanical stirrer, thermometer and an additionfunnel (14 g) 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile and150 mL chloroform were added. (10 g) phenol was added into the reactionmixture. The reaction mixture was stirred for 15 min and 5 mLtriethylamine was added at 20-30° C. The reaction mixture was heated toreflux for 15 min. (10 g)1-((3-fluoro-4-(methylcarbamoyl)-phenyl)amino)cyclobutane-1-carboxylicacid was added. The reaction mixture was refluxed for 6 hours. After thecompletion of the reaction, the reaction mixture was concentratedcompletely at 50° C. U/V. 20 mL isopropyl alcohol was added to theconcentered reaction mass and stirred for 60 min at 20-30° C. Thecompound was filtered, washed with 2 mL of isopropyl alcohol and driedto obtain 14.6 g of apalutamide with 99.82% purity having diketoimpurity-A <0.1% by HPLC.

Example-16: Purification of Apalutamide

In a 500 mL four necked round bottomed flask equipped with nitrogenatmosphere facility, mechanical stirrer, thermometer and an additionfunnel (12 g) apalutamide and (180 mL) isopropyl alcohol were added at20-30° C. The reaction mixture was heated to reflux to obtain clearsolution. (240 mg) activated Norit-A carbon. The reaction mixture wasstirred for 15 to 30 min at 70-75° C. The reaction mixture was cooled to20-30° C. and stirred for 1 hour. The apalutamide was filtered, washedwith 2 mL isopropyl alcohol and dried to obtain 10.45 g apalutamide with99.85% purity by HPLC.

Example 17: Preparation of Apalutamide in Presence of2,2,2-trifluoroethanol

In a 500 mL four necked round bottomed flask equipped with nitrogenatmosphere facility, mechanical stirrer, thermometer and an additionfunnel 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (4 g) and 50mL chloroform were added. (0.68 g) 2,2,2-trifluoroethanol was added into the reaction mixture. The reaction mixture was heated to reflux andthe solution of1-((3-fluoro-4-(methylcarbamoyl)phenyl)-amino)cyclobutane-1-carboxylatetriethylammonium (5 g) in chloroform (50 mL) was added in reactionmixture. The reaction mixture was refluxed for 2 hours. After thecompletion of the reaction, the reaction mixture was filtered, washedfiltrate with water (25 mL) and concentrated organic layer at 50° C.U/V. 45 mL methanol and 5 mL water was added to the concentered reactionmass and stirred for 60 min at 0-5° C. The compound was filtered, washedwith 10 mL water and dried to obtain 3.9 g of Apalutamide with 99.55%purity by HPLC and diketo impurity 0.14% by HPLC.

Example 18: Preparation of5-isothiocyanato-3-(trifluoromethyl)-picolinonitrile

In a 1 L four necked round bottomed flask equipped with nitrogenatmosphere facility, mechanical stirrer, thermometer and an additionfunnel, 5-amino-3-(trifluoromethyl)picolinonitrile (40 g), 400 mL waterand 200 mL dichloromethane were added at 25-35° C. The reaction mixturewas stirred for 15 min and 24.6 mL thiophosgene was added. The reactionmixture was stirred for 4 hours at 35-40° C. After completion of thereaction, the layers were separated and the organic layer wasconcentrated completely U/V at 40° C. to obtain titled compound as syrupand forwarded to next step without isolation.

Example 19: Preparation of Apalutamide

In a 500 mL four necked round bottomed flask equipped with nitrogenatmosphere facility, mechanical stirrer, thermometer and an additionfunnel 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (obtained inexample-18) and 500 mL chloroform were added. (6.8 g)2,2,2-trifluoroethanol was added into the reaction mixture. The reactionmixture was heated to reflux and (50 g) solution of1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutane-1-carboxylatetriethylammonium in chloroform (500 ml) was added in reaction mixture.The reaction mixture was refluxed for 2 hours. After the completion ofthe reaction, the reaction mixture was filtered, washed the filtratewith water (250 ml) and concentrated organic layer at 50° C. U/V. 450 mLmethanol and 50 ml water was added to the concentered reaction mass andstirred for 60 min at 0-5° C. The compound was filtered, washed with 150mL mixture of aqueous methanol and dried to obtain 38.7 g of Apalutamidewith 99.67% purity by HPLC and diketo impurity 0.05% by HPLC.

While the present invention has been described in terms of its specificembodiments, certain modification and equivalents will be apparent tothose skilled in art and the intended to be included within the scope ofthe invention.

We claim:
 1. A process for the preparation of apalutamide of Formula(I),

the process comprising: reacting a compound of Formula (II′), or saltsthereof,

wherein R is hydrogen or C₁-C₅ alkyl, with a compound of Formula (III),

in the presence of an alcohol or phenol to obtain the apalutamide ofFormula (I).
 2. The process according to claim 1, wherein the alcohol orphenol is 2,2,2-trifluoro ethanol methanol, ethanol, n-propyl alcohol,isopropyl alcohol, cyclohexanol, isobutyl alcohol, tert-amyl alcohol,butanol, pentanol, hexadecanol, ethane-1,2-diol, propane-1,2-diol,phenol, cresol, or mixture thereof.
 3. The process according to claim 1,wherein the compound of Formula (II′) is prepared by a processcomprising reacting a compound of Formula (IV) with a compound ofFormula (V);

wherein, R₁ and R₂ are either a leaving group or amine andinterchangeable, with a proviso that both R₁ and R₂ are not same, andwherein the leaving group is F, Cl, Br, I, OTs, OTf, or OMs and R ishydrogen or C₁-C₅ alkyl optionally, converting the compound of Formula(II′) to salts thereof.
 4. The process according to claim 1, wherein thecompound of Formula (II′) is compound of Formula (Hs),


5. A process for the preparation of apalutamide, the process comprisingreacting a compound of Formula (Hs),

with a compound of Formula (III),

in the presence of alcohol or phenol or mixture thereof to obtainapalutamide of Formula (I).
 6. The process according to claim 5, whereinthe alcohol or phenol is 2,2,2-trifluoro ethanol methanol, ethanol,n-propyl alcohol, isopropyl alcohol, cyclohexanol, isobutyl alcohol,tert-amyl alcohol, butanol, pentanol, hexadecanol, ethane-1,2-diol,propane-1,2-diol, phenol, cresol, or mixture thereof.
 7. The processaccording to claim 1, wherein the process comprising: reacting acompound of Formula (IV) with a compound of Formula (V) to obtain acompound of Formula (II′);

wherein, R₁ and R₂ are either a leaving group or amine andinterchangeable, with a proviso that both R₁ and R₂ are not same, andwherein the leaving group is F, Cl, Br, I, OTs, OTf, or OMs and R ishydrogen or C₁-C₅ alkyl; optionally, converting the compound of Formula(II′) to salts thereof; reacting5-amino-3-(trifluoromethyl)picolinonitrile with thiophosgene to obtaincompound of Formula (III); and

reacting the compound of Formula (III) in-situ with the compound ofFormula (II′) or salts thereof in the presence of an alcohol or phenolto obtain apalutamide of Formula (I).
 8. The process as claimed in claim7, wherein the compound of Formula (II′) or salts thereof is thecompound of Formula (Hs),


9. The process as claimed in claim 7, wherein the compound of Formula(III) is not isolated and reacted in-situ with compound of Formula (II′)or salts thereof.
 10. The process as claimed in claim 7, wherein thealcohol or phenol is selected from 2,2,2-trifluoroethanol methanol,ethanol, n-propyl alcohol, isopropyl alcohol, cyclohexanol, isobutylalcohol, tert-amyl alcohol, butanol, pentanol, hexadecanol,ethane-1,2-diol, propane-1,2-diol, phenol, cresol, or mixture thereof.